Substituted bis-(4-aminophenyl)-sulfones

ABSTRACT

Disclosed are substituted bis(4-aminophenyl)-sulfones of general formula ##STR1## wherein R 1  is hydrogen, alkyl or cycloalkyl; group, 
     R 2  is hydrogen or C 1  -C 3  alkyl, 
     R 3  is nitrile, C 1  -C 3  alkylaminocarbonyl, di C 1  -C 3  alkylaminocarbonyl, C 3  -C 7  N-cycloalkyl-C 1  -C 3  alkylaminocarbonyl C 1  -C 3  alkylamino, C 1  -C 3 , di alkylaminocarbonyl alkoxy, alkylaminosulfonyl, di C 1  -C 3  alkylaminono, diC 1  -C 3  alkylaminosulfonyl, hydroxy C 1  -C 3  alkyl, C 1  -C 3  alkylcarbonyl, amino C 1  -C 3  alkyl or C 1  -C 3  alkoxy C 1  -C 3  alkyl group 
     or, when R 1  and R 2  are each hydrogen, R 3  can be hydroxy, hydroxycarbonyl C 1  -C 3  alkoxy or di C 1  -C 3  aminocarbonylalkoxy; 
     or, when R 1  is C 1  -C 3  alkyl or C 1  -C 3  cycloalkyl and R 2  is hydrogen or C 1  -C 3  alkyl, R 3  can also be halogen, trifluoromethyl, nitro, amino, aminosulfonyl, aminocarbonyl, C 1  -C 3  alkyl, carboxy or C 1  -C 3  alkoxycarbonyl; and 
     R 4  is hydrogen or, when R 1  and R 2  are each hydrogen and R 3  is halogen or hydroxy, R 4  can also be halogen, hydroxy or C 1  -C 3  alkoxy; or a nontoxic, pharmaceutically acceptable salt thereof. Also disclosed are pharmaceutical compositions comprising such compounds alone and in combination with dihydrofolic acid-reductase inhibitors. The compounds and compositions are useful for their inhibiting effect on bacteria, mycobacteria and plasmodia.

This is a continuation of application Ser. No. 732,024, filed May 8,1985 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the field of compounds useful forinhibiting bacteria, mycobacteria and plasmodia, particularly to sulfonecompounds which are useful in this regard and in treating animals andhumans suffering from infections of such organisms.

2. Brief Information Disclosure Statement

U.S. Pat. No. 2,385,899 describes the compoundbis-(4-aminophenyl)-sulfone which has an inhibiting effect on the growthof bacteria, mycobacteria and plasmodia.

SUMMARY OF THE INVENTION

The present invention provides substituted bis-(4-aminophenyl)-sulfonesof formula I ##STR2## wherein R₁ is hydrogen, C₁ -C₇ alkyl or C₃ -C₇cycloalkyl;

R₂ is hydrogen or C₁ -C₃ alkyl;

R₃ is nitrile, C₁ -C₃ alkylaminocarbonyl, di C₁ -C₃ alkylaminocarbonyl,C₃ -C₇ N-cycloalkyl C₁ -C₃ alkylaminocarbonyl, C₁ -C₃ alkylamino, di C₁-C₃ alkylamino, di C₁ -C₃ alkylaminocarbonyl, C₁ -C₃ alkoxy, C₁ -C₃alkylaminosulfonyl, di C₁ -C₃ alkylaminosulfonyl, hydroxy C₁ -C₃ alkyl,C₁ -C₃ alkylcarbonyl, amino C₁ -C₃ alkyl or C₁ -C₃ alkoxy C₁ -C₃ alkyl

or, when R₁ and R₂ are each hydrogen, R₃ can be hydroxy orhydroxycarbonyl C₁ -C₃ alkoxy

or, when R₁ is C₁ -C₃ alkyl or C₃ -C₇ cycloalkyl and R₂ is hydrogen orC₁ -C₃ alkyl, R₃ can also be halogen, trifluoromethyl, nitro, amino,aminosulfonyl, aminocarbonyl, C₁ -C₃ alkyl, carboxy or C₁ -C₃alkoxycarbonyl; and

R₄ is hydrogen, or when R₁ and R₂ are each hydrogen and R₃ is halogen orhydroxy in the 2-position, R₄ can also be halogen, hydroxy or C₁ -C₃alkoxy, or a nontoxic, pharmaceutically acceptable salt thereof.

One subgeneric aspect includes compounds of formula I wherein:

R₁ is hydrogen, C₁ -C₇ alkyl or a C₄ -C₇ cycloalkyl;

R₂ is hydrogen or methyl;

R₃ is nitrile, methylaminocarbonyl, N-cyclohexyl-methylaminocarbonyl,methylamino, dimethylamino, dimethylaminocarbonylmethoxy, hydroxymethyl,hydroxyethyl, methylcarbonyl, aminocarbonyl or methoxymethyl;

or when, R₁ and R₂ are each hydrogen, R₃ can also be hydroxy orhydroxycarbonylmethoxy

or, when R₁ is alkyl or cycloalkyl and R₂ is hydrogen or methyl, R₃ canalso be chlorine, bromine, methyl, trifluoromethyl, nitro, amino oraminocarbonyl; and

R₄ is hydrogen or, when R₁ and R₂ are each hydrogen and R₃ is hydroxy,chlorine or bromine in the 2-position, R₄ can also be chlorine, bromine,hydroxy or methoxy, or a nontoxic, pharmaceutically acceptable saltsthereof.

A further subgeneric aspect includes compounds of formula I wherein:

R₁ is hydrogen, C₁ -C₃ alkyl or C₄ -C₇ cycloalkyl;

R₂ is hydrogen or, when R₁ is methyl, R₂ can also be methyl;

R₃ is chlorine, bromine, methyl, trifluoromethyl, hydroxymethyl,hydroxyethyl, methylamino, dimethylamino, cyano or methylcarbonyl in the2-position; and

R₄ is hydrogen; or a nontoxic, pharmaceutically acceptable addition saltthereof.

The present invention thus relates to the compounds of formula I above,the addition salts thereof, particularly the acid addition salts thereofwith pharmaceutically acceptable inorganic or organic acids,pharmaceutical compositions containing these compounds including theiraddition salts, their preparation and the use thereof for inhibitingbacteria, mycobacteria and plasmodia and for treating animals and humanssuffering from infections of such organisms.

This invention further relates to combinations of the substitutedbis(4-aminophenyl)-sulfones of formula I including their nontoxic,pharmaceutically acceptable addition salts with a dihydrofolicacid-reductase inhibitor such as pyrimethamine, trimethoprim ortrimethoprim derivatives.

DETAILED DESCRIPTION OF THE INVENTION

Examples of groups R₁ to R₄ include the following.

R₁ can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

R₂ can be hydrogen, methyl, ethyl, n-propyl or isopropyl.

R₃ can be cyano, methylaminocarbonyl, ethylaminocarbonyl,isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl,di-n-propylaminocarbonyl, N-methylethylaminocarbonyl,N-methyl-cyclopentylaminocarbonyl, N-methyl-cyclohexylaminocarbonyl,N-methyl-cycloheptylaminocarbonyl, N-ethyl-cyclohexylaminocarbonyl,methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino,diethylamino, diisopropylamino, N-methyl-ethylamino,N-ethyl-n-propylamino, dimethylaminocarbonylmethoxy,diethylaminocarbonylmethoxy, 2-dimethylaminocarbonylethoxy,2-diethylaminocarbonylethoxy, methylaminosulfonyl, ethylaminosulfonyl,isopropylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl,hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl,3-hydroxypropyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl,aminomethyl, 2-aminoethyl, 3-aminopropyl, methoxymethyl, 2-methoxyethyl,ethoxymethyl, 2-ethoxyethyl, n-propoxymethyl, 2-n-propoxyethyl, hydroxy,hydroxycarbonylmethoxy, 2-hydroxycarbonylethoxy,3-hydroxycarbonylpropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy,trifluoromethyl, nitro, amino, aminosulfonyl, aminocarbonyl, methyl,ethyl, n-propyl, isopropyl, carboxy, methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, fluorine, chlorine, bromine oriodine.

R₄ can be hydrogen, fluorine, chlorine, bromine, iodine, hydroxy,methoxy, ethoxy or n-propoxy.

According to the invention the compounds of formula I can be obtained bythe following processes.

Method A

In one method, compounds of formula I are made by reduction of acompound of formula II ##STR3## wherein R₃ and R₄ are as previouslydefined, one of A and B is nitro and the other is ##STR4## wherein R₁and R₂ are as previously defined, or is also nitro.

The reduction is conveniently carried out in a solvent or mixture ofsolvents such as water, methanol, ethanol, glacial acetic acid, ethylacetate, dimethylformamide, water/ethanol or water/tetrahydrofuran inthe presence of a reduction agent, e.g. with hydrogen in the presence ofan hydrogenation catalyst such as Raney nickel, platinum orpalladium/charcoal, with metals such as iron, tin or zinc in thepresence of an acid such as hydrochloric or acetic acid, with salts suchas iron(II)sulphate, tin(II)chloride/hydrochloric acid or sodiumdithionite in the presence of a base such as sodium hydroxide solutionor pyridine or with hydrazine in the presence of Raney nickel, attemperatures of 0° to 50° C., preferably at ambient temperature.

Method B

In another method, one or two protecting groups are cleaved from acompound of formula III ##STR5## wherein R₃ and R₄ are as previouslydefined, E is amino, C₁ -C₇ alkylamino or C₃ -C₇ cycloalkylaminoprotected by a protecting group, or is ##STR6## wherein R₁ and R₂ are aspreviously defined; and

G is an amino group optionally protected by a protecting group. At leastone of E and G must be one of the above-mentioned groups protected by aprotecting group.

Suitable protecting groups are the protecting groups conventionally usedfor amino groups, e.g. hydrolytically removable protecting groups suchas acetyl, propionyl, benzoyl, p-toluenesulfonyl, methanesulfonyl orethoxycarbonyl, or hydrogenolytically removable groups such as benzyl.

Any protecting group used is preferably split off by hydrolysis, e.g.with an acid such as hydrochloric, sulphuric or phosphoric acid or witha base such as sodium hydroxide or potassium hydroxide in a suitablesolvent or a mixture of solvents such as water, water/methanol, ethanol,water/ethanol, water/isopropanol or water/dioxan at temperatures of -10°to 120° C., preferably ambient temperature to the boiling temperature ofthe reaction mixture, or by hydrogenolysis, e.g. with hydrogen in thepresence of a hydrogenation catalyst such as palladium/charcoal in asuitable solvent such as methanol, ethanol, glacial acetic acid, ethylacetate, dioxan or dimethylformamide at temperatures of 0° to 50° C.,preferably at ambient temperature.

Method C

Compounds of formula I wherein R₃ is cyano are prepared by dehydrationof a compound of formula IV ##STR7## wherein R₁, R₂ and R₄ are aspreviously defined.

The dehydration is conveniently carried out with a dehydrating agentsuch as phosphorus pentoxide, concetrated sulphuric acid,p-toluenesulphonic acid, thionylchloride, phosphorus oxychloride,sulfurylchloride, phosphoric acid or dicyclohexylcarbodiimide,optionally in a solvent such as methylene chloride, phyridine orchlorobenzene or in an excess of the dehydrating agent used such asthionyl chloride, phosphorus oxychloride, sulfurylchloride, orphosphoric acid at temperatures of 0° to 100°, preferably 20° to 80° C.However, the reaction can also be carried out without a solvent.

Method D

Compounds of formula wherein R₃ is hydroxycarbonylalkoxy ordialkylaminocarbonyl-alkoxy can be prepared by alkylation of a compoundof formula V ##STR8## wherein R₁, R₂ and R₄ are as previously definedwith a compound of formula VI

    X--Alk--CO--R.sub.5                                        (VI)

wherein

Alk is a C₁ -C₃ alkylene;

R₅ is hydroxy, C₁ -C₃ alkoxy or di C₁ -C₃ alkylamino; and

X is a nucleophilically exchangeable group such as chlorine or bromine,optionally with subsequent hydrolysis.

The reaction is preferably carried out in a solvent such asdiethylether, tetrahydrofuran, dioxan, methanol, ethanol, pyridine ordimethylformamide, optionally with a base such as sodium hydride,potassium hydride, potassium carbonate or potassium tert.butoxide attemperatures of 0° to 75° C. preferably at ambient temperature.

The optional subsequent hydrolysis is preferably carried out either withan acid such as hydrochloric, sulphuric, phosphoric or trichloroaceticacid or with a base such as sodium hydroxide or potassium hydroxide in asuitable solvent such as water, water/methanol, ethanol, water/ethanol,water/isopropanol or water/dioxan at temperatures of -10° C. to 120° C.,e.g. ambient temperature to the boiling temperature of the reactionmixture.

Method E

Compounds of formula I wherein R₃ is aminocarbonyl, alkylamino-carbonyl,dialkylaminocarbonyl or dialkylaminocarbonylalkoxy can be prepared byreaction of a compound of formula VII. ##STR9## wherein R₁, R₂ and R₄are as hereinbefore defined; and

R₃ ' is hydroxycarbonyl, hydroxycarbonyl-alkoxy or a reactive derivativethereof, with an amine of formula VIII ##STR10## wherein R₆ is hydrogenatom or C₁ -C₃ alkyl; and

R₇ is hydrogen or C₁ -C₃ alkyl, or reactive derivatives thereof.

The reaction is conveniently carried out in a solvent such as methylenechloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran,dioxan, benzene, toluene, acetronitrile or dimethylformamide, optionallyin the presence of an acid-activating agent or a dehydrating agent, e.g.in the presence of ethylchloroformate, thionylchloride, phosphorustrichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,N,N'-dicyclohexylcarbodiimide/N-hydroxy succinimide,N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, or an agent which activates theamino group, e.g. phosphorus trichloride, and optionally in the presenceof an inorganic base such as sodium carbonate or a tertiary organic basesuch as triethylamine or pyridine, which can simultaneously serve assolvent, at temperatures of -25° C. to 250° C., preferably -10° C. tothe boiling temperature of the solvent used. The reaction can also becarried out without a solvent and furthermore any water formed duringthe reaction can be removed by azeotropic distillation, e.g. by heatingwith toluene using a water separator or by adding a drying agent such asmagnesium sulphate or molecular sieve.

In this reaction it can also be advantageous to prepare an activatedderivative of a compound of formula VII or VIII in the reaction mixtureinitially and then react this derivative with a compound of formula VIIIor VII.

Method F

Compounds of formula I wherein R₃ is hydroxymethyl, aminomethyl or1-hydroxyalkyl can be prepared by reduction of a compound of formula IX##STR11## wherein R₁ and R₂ and R₄ are as previously defined; and

R₃ " is hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl or C₂ -C₄alkylcarbonyl.

The reaction is preferably carried out with a metal hydride such assodium borohydride, lithium aluminium hydride or diborane in a solventsuch as water, methanol, water/methanol, diethyl ether, tetrahydrofuranor dioxan at temperatures of 0° to 80° C., preferably ambienttemperature to 70° C.

Method G

Compounds of formula I wherein R₁ is alkyl or cycloalkyl and R₂ ishydrogen can be prepared by reduction of a compound of formula X##STR12## wherein R₃ and R₄ are as previously defined;

L is amino or nitro; and

R₈ and R₉ together with the carbon atom between them are a C₁ -C₇alkylidene or a C₃ -C₇ cycloalkylidene.

The reduction is preferably carried out in a suitable solvent such asmethanol, ethanol, methanol/water, ethyl acetate, tetrahydrofuran ordioxan with nascent or catalytically activated hydrogen or with ahydride such as diborane, sodium borohydride or lithium aluminiumhydride at temperatures of 0° to 50° C., preferably at ambienttemperature.

If L is nitro, the reduction is particularly advantageously carried outin a solvent such as methanol or ethyl acetate with hydrogen in thepresence of a hydrogenation catalyst such as platinum orpalladium/charcoal and under a hydrogen pressure of 0 to 5 bar or with acomplex metal hydride such as lithium aluminium hydride or diborane attemperatures of 0° to 50° C., preferably at ambient temperature.

If L in a compund of formula X is amino, the reduction is carried outparticularly advantageously in a solvent such as methanol,methanol/water, tetrahydrofuran or dioxan with a complex metal hydridesuch as sodium borohydride or lithium aluminium hydride at temperaturesof 0° to 50° C., preferably at ambient temperature.

If a compound of formula I is obtained wherein R₃ is alkoxycarbonyl oralkoxycarbonylalkoxy, it can be converted by hydrolysis into acorresponding compound of formula I wherein R₃ is hydroxycarbonyl orhydroxycarbonylalkoxy. If a compound of formula I is obtained hwerein R₃and/or R₄ is chlorine or bromine, it can be converted by hydrolysis oralcoholysis into a corresponding compound of formula I wherein R₃ ishydroxy or alkoxy in the 2 position and R₄ is chlorine or bromine.

This hydrolysis is conveniently carried out either with an acid such ashydrochloric or sulphuric acid or with a base such as sodium hydroxideor potassium hydroxide in a suitable solvent such as water,water/methanol, ethanol, water/ethanol, water/isopropanol orwater/dioxan at temperatures of -10° C. to 120° C., e.g. at temperaturesof ambient temperature to the boiling temperature of the reactionmixture.

The alcoholysis is conveniently carried out in a corresponding alcoholas the solvent such as methanol, ethanol or propanol, optionally in apressure vessel, preferably with a base such as sodium hydroxide orpotassium hydroxide at temperatures of 20° C. to 200° C., preferably 50°to 180° C.

The compounds of general formulae II to X used as starting materials areknown from the literature or can be obtained by methods known from theliterature.

Thus, for example, a compound of formula II or III can be obtained byreacting an alkali metal salt of a correspondingacylaminophenyl-sulfinic acid with a corresponding p-halonitrobenzene. Acompound of formula XI ##STR13## optionally obtained after splitting offan acyl protecting group, wherein R₃ and R₄ are as previously defined,can subsequently be converted by reductive amination into a compound offormula II or after tosylation, subsequent alkylation and reduction ofthe nitro group and optionally subsequent acylation into a compound offormula III.

Moreover, a compound of formula XII ##STR14## prepared by methods knownfrom the literature, wherein R₃ and R₄ are as previously defined andAcyl is an organic acyl group, can be converted by reductive aminationor by reduction of a Schiff's base obtained after reaction with acorresponding carbonyl compound into a compound of formula III wherein Dis an aminoacyl group and E is ##STR15## wherein, R₁ and R₂ are aspreviously defined.

Moreover a compound of formula XIII ##STR16## wherein R₁ to R₄ are aspreviously defined and Na is a sodium ion, can be reacted with a4-halonitrobenzene to form a corresponding diphenylsulfone of formulaIII.

A cycloalkylamino compound of formula II, however, is preferablyobtained by reductive amination of a corresponding amino compound with acycloalkanone in the presence of sodium cyanoborohydride or by reductionof the corresponding Schiff's base with a complex metal hydride.

A compound of formula X used as starting material is obtained byreacting a corresponding compound of formula XI with a correspondingcarbonyl drivative, optionally in the presence of titanium(IV) chlorideand optional subsequent reduction of the nitro group, for example withcatalytically activated hydrogen.

As already mentioned hereinbefore, the new compounds of formula Iincluding their nontoxic, pharmaceutically acceptable addition saltshaving an inhibiting effect on the growth of bacteria and parasites suchas plasmodia and mycobacteria which is believed to be due to theirinhibiting effect on 7,8-dihydropteroic acid-synthetase.

For example, the following compounds

A=4-Ethylamino-4'-amino-2-chloro-diphenylsulfone,

B=4'-Amino-2-chloro-4-isopropylamino-diphenylsulfone,

C=4-Ethylamino-4'-amino-2-methyl-diphenylsulfone,

D=4-Ethylamino-4'-amino-2-trifluoromethyl-diphenyl-sulfone,

E=4,4'-Diamino-2-hydroxymethyl-diphenylsulfone,

F=4,4'-Diamino-2-(1-hydroxyethyl)-diphenylsulfone,

G=4,4'-Diamino-2-(N,N-dimethylamino)-diphenylsulfone,

H=4,4'-Diamino-2-(N-methylamino)-diphenylsulfone,

I=4,4'-Diamino-2-cyano-diphenylsulfone,

K=4,4'-Diamino-2-methylcarbonyl-diphenylsulfone,

L=4'-Amino-2-methyl-4-methylamino-diphenylsulfone and

M=4'-Amino-2-methyl-4-propylamino-diphenylsulfone were tested for theirbiological activity in cell-free enzyme extract of Plasmodiumberghei asfollows.

1. Preparation of the enzyme extract

Plasmodia are isolated from mouse blood infected with Plasmodium bergheiin accordance with the following reference (Heidrich, H.-G. et al., Z.Parasitenkd. 59: 151 (1979). The plasmodia were opened by ultrasound.Proteins with 7,8-hydropteroic acid synthetase activity are concentratedby gel filtration.

2. Biological test system

The inhibiting effect on 7,8-dihydropteroic acid synthesis of plasmodiais determined as follows:

Under optimum reaction conditions, i.e. V_(max) for the reaction whichis to be inhibited, the concentration of inhibitor in the new compoundsresulting in a 50% reduction in the enzyme synthesis performance isdetermined. For this purpose the quantity of 7,8-dihydropteroic acidsynthesised from the enzyme extract is determined by means of highperformance liquid chromatography (HPLC) using a UV detector after anincubation period of 4 hours. It was established that the synthesis of7,8-dihydropteroic acid proceeded in a linear manner during this period.

The i₅₀ values obtained by this method for a selection of the compoundsclaimed and those of the comparison preparations bis(4-aminophenyl)sulfone (Dapsone®, DDS) and N¹-(5,6-dimethoxy-4-pyrimidinyl)-sulfanilamide (Fanasil®) are given in thefollowing Table:

    ______________________________________                                               Substance                                                                             i.sub.50 [μM]                                               ______________________________________                                               A       2.10                                                                  B       2.67                                                                  C       2.62                                                                  D       5.86                                                                  E       4.90                                                                  F       10.40                                                                 G       12.90                                                                 H       4.10                                                                  I       12.48                                                                 K       12.90                                                                 L       2.94                                                                  M       2.44                                                                  Dapsone ®                                                                         12.41                                                                 Fanasil ®                                                                         200                                                            ______________________________________                                    

Moreover, in contrast to Dapsone®, the new compounds are well toleratedand in particular show a very low methemoglobin formulation. Forexample, when substances I and M are administered to cats in a dosage of200 mg/kg by oral route no methemoglobin formulation is detected.

On the basis of their biological properties the new compounds and thenontoxic, pharmaceutically acceptable acid addition salts thereof aresuitable for the treatment of bacterial diseases, malaria and leprosy.

In monotherapy the single dosage for adults is from 100 to 300 mg,preferably 100 to 200 mg, once or twice a day. In combined therapy witha dihydrofolic acid-reductase inhibitor the single dose for adults is 50to 200 mg+5 to 30 mg of pyrimethamine, preferably 50 to 150 mg+6.25 to25 mg of pyrimethamine.

The new compounds and the nontoxic, pharmaceutically acceptable acidaddition salts thereof optionally combined with a dihydrofolic acidreductase inhibitor such as pyrimethamine, trimethoprim or atrimethoprim derivative, can be made into preparations such as plain orcoated tablets, capsules or suspensions.

The following Examples illustrate the invention:

EXAMPLE 1 3-Cyano-4,4'-diamino-diphenylsulfone (a)3-Cyano-4,4'-dinitro-diphenylsulfide

(a) First, 4-nitrothiophenol (10 g, 0.064 mol) is dissolved by stirringin a solution of sodium hydroxide (2.8 g) in water (10 ml) and ethanol(100 ml). Then, 5-chloro-2-nitrobenzonitrile (11.8 g, 0.064 mol) isadded in order to reflux the resulting solution for 1 hour withstirring, whereupon a yellow substance is precipitated. After thesuspension has been cooled the product obtained is suction filtered,washed with ethanol and then dried. This crude product is recrystallisedfrom methanol.

Yellow crystals, m.p. 123°-126° C.,

(b) 3-Cyano-4,4'-dinitro-diphenylsulfone

Next, the 3-cyano-4,4'-dinitro-diphenylsulfide (10 g, 0.033 mol) isdissolved by heating in glacial acetic acid (150 ml). Perhydrol (20 ml)is added dropwise to this solution with stirring at ambient temperature.After it has all been added the mixture is refluxed for a further 11/2hours during which a white substance is precipitated. After thesuspension has cooled the substance is suction filtered, washed withethanol and water and then dried.

Yellow crystals, m.p.: 188°-190° C.

(c) 3-Cyano-4,4'-diamino-diphenylsulfone

The 3-cyano-4,4'-dinitro-diphenyl-sulfone (2 g, 0.006 mol) is added inbatches, with stirring, at 10° to 20° C., to a mixture of SnCl₂ ×2H₂ O(8.1 g) and conc. hydrochloric acid (15 ml). After it has all beenadded, the mixture is stirred for a further 4 hours at ambienttemperature and then the mixture is stirred into 10N sodium hydroxidesolution (50 ml) while being intensively cooled. The productprecipitated is suction filtered and dried. The crude product ispurified by column chromatography. For this, the substance is dissolvedin ethyl acetate and chromatographed over silica gel (200 g, 0.063-0.2mm), ethyl acetate and methylene chloride 1:1 being used as eluant. Thecorresponding fractions are combined and evaporated. Colorless crystals,m.p.: 240°-242° C.

EXAMPLE 2 4,4'-Diamino-2,6-dibromo-diphenylsulfone (a)3,4,5-Tribromonitrobenzene

At 20° C., with stirring and cooling with ice, a solution of2,6-dibromo-4-nitro-aniline (47.2 g) in acetic acid (1.6 liters) isslowly poured into a solution of sodium nitrite (12 g) in concentratedsulphuric acid (85 ml). Then, the mixture is stirred for 20 minutes atambient temperature. The solution thus prepared is then slowly addedwith stirring and cooling with ice to a solution of copper (I) bromide(12.8 g) in 63% hydrobromic acid (40 ml)/. After it has all been addedthe mixture is stirred for a further 30 minutes. It is diluted withwater, the precipitate is filtered off and washed with water. This crudeproduct is recrystallized from methanol.

Colorless crystals, m.p. 110° C.

(b) 4'-Acetamino-2,6-dibromo-4-nitro-diphenylsulfide

Sodium (2.9 g) is dissolved in absolute ethanol (520 ml). Then,4-acetamino-thiophenol (22 g) is dissolved in the sodium alkoxidesolution this prepared, and 3,4,5-tribromonitrobenzene (44.5 g) isadded. The mixture is then heated to reflux temperature for 5 hours.After cooling it is poured onto water, extracted exhaustively with ethylacetate, the combined ethyl acetate extracts are washed with water,dried over sodium sulfate and evaporated down to a small volume. Thematerial precipitated is suction filtered and recrystallized frommethanol.

Colorless crystals, m.p.: 208°-209° C.

(c) 2,6-Dibromo-4,4'-dinitro-diphenylsulfone

Next, 4'-acetamido-2,6-dibromo-4-nitro-diphenylsulfide (5 g) isdissolved in glacial acetic acid (40 ml) by heating. Perhydrol (20 ml)is added dropwise to this solution at ambient temperature with stirring.After it has all been added the mixture is stirred at reflux temperaturefor a further 2 hours. On cooling, yellow crystals are precipitatedwhich are suction filtered and washed first with water and then withmethanol.

M.p.: 170°-175° C.

(d) 4,4'-Diamino-2,6-dibromo-diphenylsulfone

Tin (II) chloride dihydrate (17 g) is dissolved in concentratedhydrochloric acid (17 ml). Then,2,6-dibromo-4,4'-dinitro-diphenylsulfone (3.96 g) is added to thissolution with a spatula, with stirring, and the temperature rises toabout 50° C. The mixture is stirred for a further 2 hours and left tostand for 16 hours at ambient temperature. Then it is slowly poured into10N sodium hydroxide solution (40 ml) with stirring and cooling withice. The precipitate is filtered off and washed thoroughly with waterand then with isopropanol. Colorless crystals, m.p.: 168°-170° C.(decomp.).

EXAMPLE 3 4,4'-Diamino-2-hydroxy-6-methoxy-diphenylsulfone

First, 4,4'-diamino-2,6-dibromo-diphenylsulfone (1 g) (Example 2) isadded to potassium hydroxide (1.12 g) in water (0.15 ml) and methanol(25 ml). This mixture is heated to 150° C. under pressure for 14 hours.It is then diluted with water, the insoluble matter is filtered off andthe filtrate is concentrated to dryness in vacuo. The solid residue istaken up in a little water. The aqueous solution is acidified with 2Nhydrochloric acid up to pH 5 and the colorless precipitate obtained issuction filtered, washed with water and dried, M.p: 127° C. (decomp.).

EXAMPLE 4 2-Bromo-4,4'-diamino-6-hydroxy-diphenylsulfone

Here, 4,4'-diamino-2,6-dibromo-diphenylsulfone (1 g) Example 2) is addedto a solution of potassium hydroxide (1.12 g) in water (0.15 ml) andtert.butanol. (50 ml). This mixture is heated to 150° C. under pressurefor 10 hours. It is then diluted with water, filtered to remove theinsoluble matter and the filtrate is evaporated to dryness in vacuo. Thesolid residue is taken up in a little water. The aqueous solution isacidified with 2N hydrochloric acid up to pH 5 and the colorlessprecipitate obtained is suction filtered and washed with water anddried.

IR spectrum (KBr): 3000-3600 cm⁻¹ OH assoc., 3360, 3470 cm⁻¹ NH₂ free,3210 cm⁻¹ NH₂ assoc., 2840 cm⁻¹ OCH₃, 1140, 1320 cm⁻¹ SO₂.

EXAMPLE 5 4-Ethylamino-4'-amino-2-methyl-diphenylsulfone (a)4'-Acetamino-2-methyl-4-tosylamino-diphenylsulfide

Here, 4'-acetamino-4-amino-2-methyl-diphenyl-sulfide (2.7 g) J. Org.Chem. 15, 400 (1950)) is dissolved in dry pyridine (7 ml). At ambienttemperature, p-toluenesulfonic acid chloride (2.85 g) is added to thissolution and the mixture is left to stand for 2 days at ambienttemperature. Then it is heated to 90° C. for 6 hours to complete thereaction and after cooling, it is diluted with water (50 ml). The solidsprecipitated are suction filtered and carefully washed with water andthen with petroleum ether and dried.

M.p.: 130°-134° C.

(b) 4'-Acetamino-4-(N-ethyl-N-tosyl-amino)-2-methyl-diphenylsulfide

The 4'-acetamino-2-methyl-4-tosylamino-diphenylsulfide (3.5 g), ethyliodide (2 g) and dry potassium carbonate (1.5 g) are heated to 95° C. indimethylformamide (50 ml) with stirring for 17 hours. After cooling themixture is poured onto water. The solids precipitated are suctionfiltered and thoroughly washed with water and petroleum ether and thendried.

IR spectrum (methylene chloride): 3420 cm⁻¹ NH, 1695 cm⁻¹ amide, 1505cm⁻¹ sulfonamide.

(c) 4'-Acetamino-4-(N-ethyl-tosylamino)-2-methyl-diphenylsulfone

The 4'-acetamino-4-(N-ethyl-tosylamino)-2-methyl-diphenylsulfide (2.25g) is heated to 90° C. for 3 hours in acetic acid (20 ml) and perhydrol(6 ml). After cooling, the mixture is diluted with water, the solidsprecipitated are carefully washed with water and petroleum ether anddried. This crude product is chromatographed over silica gel with amethylene chloride/methanol mixture (25:1). Light yellow foamysubstance.

    ______________________________________                                        IR spectrum (KBr):                                                                           3420 cm.sup.-1                                                                              NH                                                              1680 cm.sup.-1                                                                              amide                                                           1500 cm.sup.-1                                                                              sulfonamide                                                     1315, 1150 cm.sup.-1                                                                        sulfone                                          ______________________________________                                    

(d) 4-Ethylamino-4'-amino-2-methyl-diphenylsulfone

The 4'-acetamino-4-(N-ethyl-tosylamino)-2-methyl-diphenylsulfone (1.05g) is dissolved in concentrated sulfuric acid (6 ml). This solution isleft to stand for 4 hours at ambient temperature, then mixed with iceand neutralized with ammonia. The solids precipitated are suctionfiltered. The crude product consisting of4'-acetamino-4-ethylamino-2-methyl-diphenylsulfone is heated to boilingtemperature for 1 hour in a mixture of concentrated hydrochloricacid/water=1/1. After cooling, it was poured onto water and neutralizedwith ammonia. The solids precipitated are washed with water and dried.

M.p.: 166°-167° C.

EXAMPLE 6 4'-Amino-2-methyl-4-methylamino-diphenylsulfone

First, 4'-acetamino-2-methyl-4-(N-methyl-tosyl-amino)-diphenylsulfone(3.5 g); prepared analogously to Example 5, is heated to refluxtemperature with phenol (3.5 g) in 48% hydrobromic acid (120 ml) for11/2 hours. After cooling, the mixture is poured onto ice, neutralizedwith sodium hydroxide, extracted with methylene chloride, dried oversodium sulfate and concentrated to dryness in vacuo. The solid residueis dissolved in absolute ethanol. This solution is acidified withethanolic hydrochloric acid and then mixed with ether untilcrystallization starts. The crystals are suction filtered, washed withethanol/ether and dried.

Dihydrochloride: colorless crystals, mp.: 232°-235° C.

M.p. of the base: 150°-153° C.

EXAMPLE 7 4'-Amino-2-methyl-4-n-propylamino-diphenylsulfone

The title compound is prepared from4'-acetamino-2-methyl-4-(N-n-propyl-tosylamino)-diphenylsulfone withphenol and hydrobromic acid analogously to Example 6.

Colorless crystals, m.p.: 170°-173° C.

EXAMPLE 8 4-Ethylamino-4'-amino-2-chloro-diphenylsulfone (a)4'-Acetamino-2-chloro-4-p-tosylamino-diphenylsulfone

Heere, p-tosyl chloride (190 mg) is dissolved in anhydrous pyridine (5ml) and 4'-acetamino-4-amino-2-chlorodiphenylsulfone (300 mg)(synthesised according to J. Med. Chem. 14:1166 (1971)) is added. Themixture is kept at ambient temperature for 3 hours with stirring and for1 hour at 50° C. After cooling, it is poured onto ice/HCl and theprecipitate is suction filtered.

Recrystallization from MeOH/H₂ O, colorless crystals.

(b) 4-Ethylamino-4'-amino-2-chloro-diphenylsulfone

Then, 4'-acetamino-2-chloro-4-p-tosylaminodiphenylsulfone (70 mg) andpotassium carbonate (25 mg) are suspended in dimethylformamide (5 ml).After the addition of ethyl iodide (200 μl) the mixture is heated to 90°C. (bath) for 24 hours. After cooling, the mixture is poured onto iceand the precipitate is removed by suction filtering. The dry residue isdissolved in conc. H₂ SO₄ (0.5 ml) with stirring. After 1 hour, it ispoured onto ice and the pH is adjusted to 4 to 6 with ammonia. Theprecipitate is suction filtered, mixed with 20% hydrochloric acid (10ml) and refluxed for 1 hour. After cooling, the mixture is neutralizedwith ammonia and the precipitate is suction filtered.

Recrystallization from MeOH/H₂ O.

M.p.: 173°-175° C.

EXAMPLE 9 4'-Amino-2-chloro-4-isopropylamino-diphenylsulfone

Here, 4'-amino-2-chloro-4-p-tosylamino diphenylsulfone (300 mg),potassium carbonate (100 mg), isopropylbromide (500 μl) anddimethylformamide (10 ml) are heated to 90° C. (bath) for 72 hours.After cooling, the mixture is poured onto ice and the precipitate issuction filtered. The dry residue is dissolved in conc. H₂ SO₄ (0.5 ml)with stirring. After 1 hour it is poured onto ice and the pH is adjustedto 4 to 6 with NH₃. The precipitate obtained is suction filtered, mixedwith 20% hydrochloric acid (10 ml) and refluxed for 1 hour. Aftercooling, it is neutralized with ammonia and the precipitate is suctionfiltered.

Recrystallization from methanol. Colorless solids.

    ______________________________________                                        NMR (DMSO) 1.08-1.15 6H    Doublet CH(CH.sub.3).sub.2                         90 MHZ     3.40-3.70 1H    Multiplet CH (CH.sub.3).sub.2                                 6.04      2H    Singlet NH.sub.2                                              6.50-6.70 5H    Multiplet NH, aromatic H                                      7.40-7.50 2H    Doublet, aromatic H                                           7.75-7.85 1H    Doublet, aromatic H                                ______________________________________                                    

EXAMPLE 10 2-Carboxymethyloxy-4,4'-diamino-diphenylsulfone (a)2-Ethoxycarbonylmethyloxy-4,4'-diamino-diphenylsulfone

First, 4,4'-diamino-2-hydroxydiphenylsulfone (7.9 g, 0.03 mol) (J.Scientific and Industrial Research 17B, 192 (1958)) is dissolved intetrahydrofuran (160 ml). This solution is mixed with sodium hydride(1.3 g, 0.03 mol) under a nitrogen atmosphere with stirring at ambienttemperature. The mixture begins to foam and toward the end of theaddition a thick crystal slurry is precipitated. By addingdimethylformamide (250 ml) a clear solution is obtained. Ethylbromoacetate (3.3 ml. 0.03 mol) is added dropwise, the mixture isstirred for 3.5 hours at ambient temperature and then evaporated todryness in vacuo. The residue is stirred with a mixture of water andmethylene chloride, whereupon a solid crystalline material is obtainedwhich is suction filtered from the solvent mixture, stirred withmethylene chloride/water once more, suction filtered again and dried.The product thus obtained has a melting point of 178° to 183° C.

(b) 2-Carboxymethyloxy-4,4'-diamino-diphenylsulfone

The 2-ethoxycarbonylmethyloxy-4,4'-diaminodiphenylsulfone (2.8 g 0.008mol) is heated to boiling for half an hour in a mixture of ethanol (280ml), sodium hydroxide (2.8 g, 0.007 mol) and water (56 ml). The mixtureis left to cool, acidified with conc. hydrochloric acid to a pH of 1 andevaporated to dryness in vacuo. Then, the residue is briefly boiled withalcohol, filtered to remove any insoluble matter, the filtrate isevaporated to dryness in vacuo and the residue is purified bychromatography on silica gel, eluant methylene chloride/methanol (1:1).The product thus obtained is recrystallized from ethanol and has amelting point of 255°-260° C. (decomp.).

EXAMPLE 114,4'-Diamino-2-dimethylamino-carbonyl-methyloxy-diphenylsulfone

First, 2-ethoxycarbonylmethyloxy-4,4'-diaminodiphenylsulfone (3.4 g,0.0097 mol) is dissolved in a mixture of aqueous 40% dimethylaminesolution (68 l ml) and tetrahydrofuran (100 ml). This solution is leftto stand for 3 hours at ambient temperature, then evaporated to drynessin vacuo. The residue obtained is triturated with water (100 ml). Thesolid material is suction filtered and recrystallized from ethanol. Theproduct thus obtained has a melting point of 238°-224° C. (decomp.).

EXAMPLE 12 4,4'-Diamino-2-methoxymethyl-diphenylsulfone (a)2-Hydroxymethyl-4-nitro-chlorobenzene

First, 2-carboxy-4-nitro-chlorobenzene (43.2 g, 0.215 mol) is dissolvedin absolute tetrahydrofuran (500 ml), then triethylamine (30 ml, 0.215mol) is added thereto. This mixture is cooled to -10° C. and, at thistemperature, carbethoxy chloride (22 ml, 0.229 mol) is added dropwisethereto. The resulting mixture is stirred for a further hour at -10° to-5° C. The triethylamine hydrochloride formed is filtered off. Thetetrahydrofuran solution is added dropwise over a period of 10 minutesat 0° C. to a solution of sodium borohydride (30 g, 0.789 mol) in water(100 ml). The reaction mixture is allowed to come back to ambienttemperature with stirring within an hour. The reddish-orange solutionobtained is mixed with 2N hydrochloric acid while cooling with ice andthen extracted with ether. The ether extract is washed with water. Afterthe ether has been evaporated off an oil remains which recrystallizesafter some time.

IR spectrum (methylene chloride): 3610 cm⁻¹ OH, 1375 cm⁻¹ NO₂.

(b) 2-Methoxymethyl-4-nitro-chlorobenzene

The 2-hydroxymethyl-4-nitrochlorobenzene (18.7 g, 0.1 mol) is dissolvedin absolute tetrahydrofuran (500 ml) and cooled to 0° C. The sodiumalkoxide of the above compound is prepared with sodium hydride (4.8 g,0.1 mol) (55% in oil). After 1 hour's reaction methyl iodide (14.2 g,0.1 mol) is added dropwise with stirring at 0° C. The reaction mixtureis kept at 0° C. for a further 3 hours with stirring. Then it is stirredwithout a cooling bath until ambient temperature is reached. The solventis then evaporated off and the residue is taken up in ethyl acetate, theethyl acetate phase is washed with water, dried and concentrated todryness in vacuo. The remaining oil is crystallized from ethyl acetate.

    ______________________________________                                        NMR (CDCL.sub.3 /CD.sub.3 OD):                                                                3.6 ppm      3H Singlet                                                       4.6 ppm      2H Singlet                                       80 MHz          7.5-8.75 ppm 3H Multiplet                                     ______________________________________                                    

(c) 4'-Acetylamino-4-nitro-2-methoxymethyl-diphenylsulfone

Next 4-acetylanilido sulfinic acid (6.5 g, 0.0327 mol) is suspended inethanol (50 ml) and sodium hydride (1.5 g, 0.033 mol) (55% in oil) isadded in batches with stirring. The resulting sodium salt of the aboveacid is precipitated with ether and dried. Then, 4-acetylanilido sodiumsulfinate (6.6 g, 0.03 mol) is refluxed with2-methoxymethyl-4-nitro-chlorobenzene (6.1 g, 0.03 mol) indimethylformamide (25 ml) for 5 hours. The reaction mixture is thenpoured onto ice water and extracted with ethyl acetate. The ethylacetate extract is washed twice with water, dried over sodium sulfateand the ethyl acetate is evaporated off in vacuo. The solid residue iswashed with isopropanol and petroleum ether.

    ______________________________________                                        IR spectrum (CH.sub.2 Cl.sub.2):                                                               3420 cm.sup.-1  NH                                                            1710 cm.sup.-1  CO                                                            1350 + 1530 cm.sup.-1                                                                         NO.sub.2                                     ______________________________________                                    

(d) 4'-(Acetylamino-4-amino-2-methoxymethyl-diphenylsulfone

Here, 4'-acetylamino-4-nitro-2-methoxymethyldiphenylsulfone (3.8 g,0.0104 mol) is added in batches within 15 minutes to a boiling mixtureof iron powder (3.4 g, 0.061 mol) in alcohol (25 ml), water (6 ml) and36% hydrochloric acid (0.05 ml). The mixture is then refluxed for 2hours. The reaction mixture is cooled, diluted with methanol, filteredover Celite and the methanol is evaporated. The residue is taken up inwater and extracted with ethyl acetate. Then the ethyl acetate isevaporated off and an amorphous solid product is left.

    ______________________________________                                        IR spectrum: (KBr):                                                                           1680 cm.sup.-1                                                                              Amide I                                                         1525 cm.sup.-1                                                                              Amide II                                                        1140, 1320 cm.sup.-1                                                                        SO.sub.2                                        ______________________________________                                    

(e) 4,4'-Diamino-2-methoxymethyl-diphenylsulfone

The 4'-acetylamino-4-amino-2-methoxymethyldiphenylsulfone (3.5 g, 0.01mol) is heated to boiling in 3N hydrochloric acid for 15 minutes. Thereaction solution is cooled, diluted with water and filtered. Theaqueous filtrate is adjusted to pH 8-9 with dilute aqueous ammonia. Theprecipitate obtained is filtered off and washed with water.

    ______________________________________                                        IR spectrum (KBr):                                                                              1130 cm.sup.-1                                                                             SO.sub.2                                                         1280 cm.sup.-1                                                                             SO.sub.2                                       ______________________________________                                    

EXAMPLE 13 4,4'-Diamino-2-methylcarbonyl-diphenylsulfone

The title compound is prepared from4'-acetamino-4-amino-2-methylcarbonyl-diphenylsulfone (preparedanalogously to Example 12c and 12d) with hydrochloric acid analogouslyto Example 12e.

    ______________________________________                                        IR spectrum (CH.sub.2 Cl.sub.2):                                                               3485, 3390 cm.sup.-1                                                                        NH.sub.2                                                        1695 cm.sup.-1                                                                              Ketone                                                          1290, 1140 cm.sup.-1                                                                        SO.sub.2                                       ______________________________________                                    

EXAMPLE 14 4,4'-Diamino-2-(1-hydroxyethyl)-diphenylsulfone

Here, 4,4'-diamino-2-methylcarbonyl-diphenylsulfone (1.6 g, 0.005 mol)(Example 13) suspended in 90% aqueous methanol (75 ml) is reduced withsodium borohydride (0.3 g, 0.0075 mol) at 20° C. After 30 minutes aclear solution is obtained. The methanol is evaporated off and theaqueous solution is diluted with more water. An oil is precipitatedwhich is extracted with methylene chloride. After the solvent has beenevaporated off a white amorphous product remains.

    ______________________________________                                        NMR spectrum (CDCl.sub.3):                                                                      1.3 ppm    2H Doublet                                                         5.5 ppm    1H Multiplet                                     80 MHZ            6.6-7.9 ppm                                                                              7H Multiplet                                     ______________________________________                                    

EXAMPLE 15 4,4'-Diamino-2-cyano-diphenylsulfone

Here, 4,4'-diamino-2-carbamoyl-diphenylsulfone (6.3 g, 0.021 mol)(prepared analogously to Example 18) is refluxed for 8 hours in thionylchloride (45 ml). A yellowish-orange solution is obtained and thethionyl chloride is distilled off. A yellow foam remains which issuspended in water and made alkaline with ammonia solution. The base ofthe title compound thus obtained is suction filtered as an amorphoussolid product and washed with water. The crude product is purified bychromatography on a silica gel column. (Eluant: 8 parts methylenechloride, 1 part methanol and 1 part acetone). The correspondingfractions are freed from the eluant and yield an amorphous,yellowish-white solid product.

Mass spectrum (CH₅): M⁺ 273 m/Z.

EXAMPLE 16 4,4'-Diamino-2-aminomethyl-diphenylsulfone

Here, 4,4'-diamino-2-carbamoyl-diphenylsulfone (0.35 g, 0.0012 mol) isdissolved in absolute tetrahydrofuran (25 ml) and mixed with lithiumaluminium hydride (0.15 g, 0.0036 mol). The mixture is stirred for 1hour at 20° C. and then heated to 50° C. for 8 hours. The lithiumaluminum hydride is decomposed with ice water and the reaction mixtureis extracted with ether. After the solvent has been evaporated off, asolid yellow product is left behind, which is purified by chromatographyover a silica gel column (eluant: 6 parts methylene chloride and 1 partmethanol). After the eluant has been evaporated off from thecorresponding fractions a yellowish amorphous product is left.

Mass spectrum (CH 5): M⁺ 277 m/z.

EXAMPLE 17 4,4'-Diamino-2-hydroxymethyl-diphenylsulfone

Here, 4,4'-diamino-2-methoxycarbonyl-diphenylsulfone (0.23 g, 0.00075mol) (J. Med. Chem. 14, 1168 (1971) is dissolved in absolutetetrahydrofuran (15 ml) and mixed with lithium aluminium hydride (0.07g, 0.0019 mol). The mixture is stirred for 1 hour at 20° C. and thenheated for 3 hours to 50° C. The excess lithium aluminum hydride isdecomposed with water and then the reaction mixture is extracted withether. After the solvent has beenevaporated off, a yellowish-brown oilis left which is purified by chromatography over a silica gel column.(Eluant: 9 parts methylene chloride and 1 part methanol). Thecorresponding fractions yield a yellowish oil after evaporation of theeluant.

Mass spectrum (CH 5): M⁺ 278 m/Z.

EXAMPLE 18 4,4'-Diamino-2-(N-methylcarbamoyl)-diphenylsulfone

Here, 4,4'-diamino-2-chlorocarbonyl-diphenylsulfone-dihydrochloride(0.95 g, 0.0025 mol) is suspended in methylene chloride (15 ml) andadded to a solution of methylamine (0.31 g, 0.01 mol) in methylenechloride (20 ml). The mixture is stirred overnight at 20° C. Then themethylene chloride is evaporated off and the remaining solid residue iswashed out with water. A white amorphous residue is left.

    ______________________________________                                        IR spectrum (KBr):                                                                           3480 + 3360 cm.sup.-1                                                                         NH.sub.2                                                      1630 cm.sup.-1  Amide                                                         1125 cm.sup.-1  SO.sub.2                                       ______________________________________                                    

EXAMPLE 192-(N-Cyclohexyl-N-methyl-carbamoyl)-4,4'diamino-diphenylsulfone

The title compound is prepared from4,4'-diamino-2-chlorocarbonyl-diphenylsulfone-dihydrochloride andN-cyclohexyl-N-methylamine analogously to Example 18.

    ______________________________________                                        IR spectrum (CH.sub.2 Cl.sub.2):                                                               3490, 3400 cm.sup.-1                                                                        NH.sub.2                                                        1620-1630 cm.sup.-1                                                                         Amide                                                           1300, 1140 cm.sup.-1                                                                        SO.sub.2                                       ______________________________________                                    

EXAMPLE 20 4,4'-Diamino-2-(N,N-dimethylamino)-diphenylsulfone (a)2-Chloro-5-nitro-N,N-dimethyl-aniline

Paraformaldehyde (63 g) is placed in 35% formic acid (1 liter) at 100°C., and 2-chloro-5-nitro-aniline (60 g) in 95% formic acid (560 ml) isadded in batches. Then, the mixture is heated for 2 hours over a steambath, the reaction mixture is evaporated, mixed with 2N NaOH (560 ml)and Na₂ SO₃ (140 g), and extracted with methylene chloride. The organicphase is dried with magnesium sulfate, evaporated to dryness again andpurified by chromatography over a column filled with silica gel.(Eluant: dichloromethane/cyclohexane=2:1). Yellow oil which is reactedfurther directly.

(b) 4'-Acetamino-2-(N,N-dimethylamino)-4-nitrodiphenylsulfone

The sodium salt of 4-acetylamino-phenylsulfinic acid (24 g),2-chloro-5-nitro-(N,N-dimethyl)aniline (22 g) and absolutedimethylformamide (120 ml) are mixed together, refluxed for 28 hours,poured onto water, extracted with ethyl acetate and the organic phase isdried with magnesium sulfate and evaporated in vacuo. The residue ispurified over a column filled with silica gel (eluant:dichloromethane/methanol=50:1). The fractions containing the desiredproduct are evaporated aned the residue is triturated with ether.

Yellow crystals. M.p.: 213°-216° C.

(c) 4'-Amino-2-(N,N-dimethylamino)-4-nitro-diphenylsulfone

Next, 4'-acetamino-2-(N,N-dimethylamino)-4-nitrodiphenylsulfone (10 g)is placed in semi conc. hydrochloric acid (50 ml) and heated for about 1hour over a steam bath until a clear solution is obtained. Then it iscooled, made basic with 2N sodium hydroxide solution, extracted withdichloromethane, the organic phase is dried with magnesium sulfate andconcentrated by evaporation. The residue is purified over a columnfilled with silica gel (eluant: dichloromethane/methanol=50:1).

Yellow crystals. m.p.: 164°-166° C.

(d) 4,4'-Diamino-2-(N,N-dimethylamino)-diphenylsulfone

The 4'-amino-2-(N,N-dimethylamino)-4-nitrodiphenylsulfone (6 g) ishydrogenated in methanol (200 ml) with Raney nickel (0.6 g) for 6 hoursat ambient temperature under a pressure of 3 bar. Then the catalyst isremoved by suction filtering, the filtrate is concentrated to dryness invacuo and purified over a column filled with silica gel (eluant:dichloromethane/methanol=60:1).

Beige crystals; m.p. 196°-197° C.

EXAMPLE 21 4,4'-Diamino-2-(N-methyl-amino)diphenylsulfone

The title compound is prepared from 2-chloro-5-nitro-(N-methyl)-anilineand the sodium salt of 4-acetylaminophenylsulfinic acid anlogously toExample 20. Hardened foam.

IR spectrum (methylene chloride): 3500, 3400 cm⁻¹ NH₂, 1130, 1300 cm⁻¹SO₂.

The 2-chloro-5-nitro-N-methyl-aniline was obtained as follows. First,2-chloro-5-nitro-aniline (50 g), methyl iodide (82 g) and sodiumcarbonate (123.3 g) are refluxed for 16 hours in ethanol (1.2 liters).Then the insoluble precipitate is filtered off, the mother liquor isconcentrated by evaporation and the residue is taken up indichloromethane. The organic phase is washed with water, dried withmagnesium sulfate and concentrated in vacuo. The residue is purifiedover a column filled with silica gel (eluant:dichloromethane/cyclohexane=1:2). Orange crystals; m.p.: 106°-108° C.

EXAMPLE 22 4'-Amino-2,4-bis-(N,N-dimethyl-amino)-diphenylsulfone (a)4'-Acetamino-4-amino-2-(N,N-dimethyl-amino)diphenylsulfone

First, 4'-acetamino-2-(N,N-dimethyl-amino)-4-nitro-diphenylsulfone (4.5g) is hydrogenated in methanol (200 ml) with Raney nickel (0.45 g) fortwo hours at ambient temperature under a pressure of 3 bar. Then thecatalyst is filtered off, the filtrate is concentrated by evaporationand the residue is purified over a column filled with silica gel(eluant: dichloromethane/methanol=30:1).

Light brown crystals; m.p.: 117°-119° C.

(b) 4'-Acetamino-2,4-bis-(N,N-dimethyl-amino)diphenylsulfone

Paraformaldehyde (1.2 g) is dissolved in 95% formic acid (30 ml) withheating and 4'-acetamino-4-amino-2-(N,N-dimethyl-amino)-diphenylsulfone(2.3 g) is added. The reaction mixture is kept at 90° C. for 12 hoursand then concentrated by evaporation in vacuo. A 2N sodium hydroxidesolution (11 ml) and Na₂ SO₃ (2.7 g) are then added. The mixture isextracted with ethylacetate, the extract is treated with active charcoaland magnesium sulphate, concentrated to dryness in vacuo and the residueis purified over a column filled with silica gel. (eluant:dichloromethane/methanol=30:1). Colorless oil which is immediatelyreacted further.

(c) 4'-Amino-2,4-bis-(N,N-dimethyl-amino)-diphenylsulfone

The 4'-acetamino-2,4-bis-(N,N-dimethyl-amino)-diphenylsulfone (1 g) isdissolved in 2N hydrochloric acid (50 ml) and heated for about 45minutes over a steam bath. Then the mixture is cooled, made basic with2N NaOH and extracted with methylene chloride. The organic phase istreated with active charcoal and magnesium sulphate, concentrated todryness in vacuo and the residue is purified over a column filled withsilica gel (eluant: dichloromethane/methanol=50:1). The residue of thedesired fraction is triturated with ether.

Yellowish crystals; m.p.: 166°-168° C.

EXAMPLE 23 4'-Amino-4-(N-ethyl-amino)-2-trifluoromethyl-diphenylsulfone(a) 4'-Acetamino-4-nitro-2-trifluoromethyl-diphenylsulfone

The sodium salt of 4-acetamino-phenylsulfinic acid (50 g) and2-chloro-5-nitro-benzotrifluoride (48 g) in absolute dimethylformamide(260 ml) are refluxed for about 25 hours. The mixture is then cooled,poured onto water (2 liters) and extracted with dichloromethane. Theorganic phase is washed thoroughly with water, dried with magnesiumsulphate and concentrated to dryness in vacuo. The residue is trituratedwith ether.

Light yellow crystals; m.p.: 228°-230° C.

(b) 4'-Acetamino-4-amino-2-trifluoromethyl-diphenylsulfone

The 4'-acetamino-4-nitro-2-trifluoromethyldiphenylsulfone (30 g) ishydrogenated in methanol (800 ml) with Raney nickel (3 g) for 8 hours 40minutes at ambient temperature under a pressure of 3 bar. Then themixture is heated in order to bring the desired product into solutionagain. The catalyst is removed by suction filtering while still warm andthe filtrate is concentrated in vacuo.

Beige crystals; m.p.: 220°-224° C.

(c) 4'-Acetamino-4-(N-ethyl-amino)-2-trifluoromethyldiphenylsulfone

The 4'-acetamino-4-amino-2-trifluoromethyldiphenylsulfone (3 g),acetaldehyde (6.7 g), molten sodium acetate (0.6 g) and Raney nickel (3g) in ethanol (100 ml) are hydrogenated at 70° C. under a pressure of 5bar for 11 hours. Then the catalyst is filtered off and the filtrate isconcentrated to dryness in vacuo. The evaporation residue is purified bychromatography over a column filled with silica gel (eluant:dichloromethane/methanol=50:1).

Colorless crystals; m.p.: 157°-159° C.

(d) 4'-Amino-4-(N-ethyl-amino)-2-trifluoromethyl-diphenylsulfone

The 4'-acetamido-4-(N-ethyl-amino)-2-trifluoromethyl-diphenylsulfone(1.5 g) is stirred in semi-concentrated hydrochloric acid (20 ml) forabout 5 minutes over a steam bath until a clear solution is obtained.Then it is poured onto water (50 ml), made basic with 2N sodiumhydroxide solution and the precipitate obtained is suction filtered.This is taken up in dichloromethane. The solution is dried withmagnesium sulphate, concentrated to dryness in vacuo and the residue istriturated with ether.

Yellowish crystals; m.p.: 133°-135° C.

EXAMPLE 24 4'-Amino-4-ethylamino-2-cyano-diphenylsulfone (a)4'-Acetamino-4-amino-2-methoxycarbonyl-diphenylsulfone

The title compound of this paragraph is prepared from4'-acetamino-2-methoxycarbonyl-4-nitro-diphenylsulfate (Lit: J. Med.Chem. 1971, 1168) by catalytic hydrogenation analogously to Example 23b.

    ______________________________________                                        Spectra: IR (KBr):                                                                           3360, 3450 cm.sup.-1                                                                          NH.sub.2                                                      1735 cm.sup.-1  ester-CO                                                      1650, 1680, 1550 cm.sup.-1                                                                    amide-CO                                       UV (methanol): 257 nm and 240 nm.                                             ______________________________________                                    

(b) 4'-Acetamino-4-ethylamino-2-methoxycarbonyl-diphenylsulfone

The title compound of this paragraph is prepared from4'-acetamino-4-amino-2-methoxycarbonyl-diphenylsulfone, acetaldehyde andcatalytically activated hydrogen analogously to Example 23c.

    ______________________________________                                        Amorphous product.                                                            ______________________________________                                        Spectra: IR (CH.sub.2 Cl.sub.2):                                                              3440 cm.sup.-1                                                                              --NH                                                            1740 cm.sup.-1                                                                              ester-CO                                                        1710, 1520 cm.sup.-1                                                                        amide-CO                                        UV (methanol):  260 nm, 300 nm.                                               ______________________________________                                    

(c) 4-Ethylamino-4'-amino-2-methoxycarbonyl-diphenylsulfone

The title compound of this paragraph is prepared from4'-acetamino-4-ethylamino-2-methoxycarbonyl-diphenylsulfone andhydrochloric acid analogously to Example 23d.

M.p.: 155°-156° C.

(d) 4-Ethylamino-4'-amino-2-carboxy-diphenylsulfone

The 4-ethylamino-4'-amino-2-methoxycarbonyl-diphenylsulfone (39 g, 0.116mol) is refluxed for 4 hours with sodium hydroxide (10 g) in a mixtureof water (70 ml) and methanol (350 ml). After cooling, the mixture issuction filtered to remove a small quantity of an insoluble material.The filtrate is adjusted to pH 4 with hydrochloric acid whereupon thereaction product is precipitated in the form of crystals. These aresuction filtered, washed with ice water and dried.

M.p: 116°-122° C. (decomp.).

(e) 4-Ethylamino-4'-amino-2-cyano-diphenylsulfone

The 4-ethylamino-4'amino-2-carboxy-diphenylsulfone (37 g, 0.115 mol) isrefluxed for 45 minutes in thionyl chloride (370 ml). The mixture isconcentrated to dryness in vacuo and the residue is carefully mixed withcold concentrated aqueous ammonia. From this4-ethylamino-4'-amino-2-carbamoyl-diphenylsulfone is obtained, which issuction filtered, washed with water, dried and dehydrated without anyfurther purification with thionyl chloride to give the nitrile. Theabove amide (32 g, about 0.1 mol) in thionyl chloride (220 ml) isrefluxed for 2.75 hours. The reaction mixture is evaporated in vacuo andthe crude product is purified by repeated chromatography on silica gel(eluant: methylene chloride/methanol=40:1).

M.p.: 177°-183° C.

EXAMPLE 25 4'-Amino-2-methyl-4-n-propylamino-diphenylsulfone (a)2-Methyl-4'-nitro-4-(N-n-propyl-N-tosyl-amino)diphenylsulfone

First, 2-methyl-4'-nitro-4-tosylamino-diphenylsulfone (2.5 g), n-propyliodide (0.8 ml) and anhydrous potassium carbonate (0.9 g) are heated to60° C. for 17 hours in dimethylformamide (30 ml) with stirring. Aftercooling, the mixture is poured onto water. The solids precipitated aretaken up in methylene chloride. The methylene chloride phase isseparated, washed with water, dried over sodium sulphate andconcentrated to dryness. When the residue is recrystallized frompetroleum ether/ethyl acetate, yellow crystals are obtained:

M.p. 132°-135° C.

(b) 2-Methyl-4'-nitro-4-n-propylamino-diphenylsulfone

A solution of the2-methyl-4'-nitro-4-(N-n-propyl-N-tosyl-amino)-diphenylsulfone (2.48 g)is left to stand for 4 hours at ambient temperature in concentratedsulfuric acid (25 ml). Then, it is poured into ice/concentrated ammoniumhydroxide solution and the solids precipitated are extracted withmethylene chloride. The methylene chloride phase is washed with water,dried over sodium sulphate and concentrated to dryness in vacuo and inthis way the desired compound is obtaihed in the form of a yellow solid.

(c) 4'-Amino-2-methyl-4-n-propylamino-diphenylsulfone

The 2-methyl-4'-nitro-4-n-propylamino-diphenylsulfone (1.6 g) isdissolved in methanol (60 ml) and hydrogenated at ambient temperature inthe presence of 10% palladium/charcoal (0.5 g) under a hydrogen pressureof 50 psi. After the uptake of hydrogen has ended (15 minutes) thecatalyst is filtered off and the methanolic solution is concentrated (to10 ml). The colorless crystals precipitated, m.p. 170°-173° C., aresuction filtered.

EXAMPLE 26 4'-Amino-4-cyclohexylamino-2-methyl-diphenylsulfone (a)4-cyclohexylamino-2-methyl-4'nitro-diphenylsulfone

First, 4-amino-2-methyl-4'-nitro-diphenylsulfone is dissolved inmethylene chloride (120 ml). Molecular sieve A4 (15 g) and etherealhydrochloric acid (2 ml) are added to this solution and thencyclohexanone (2 ml) and sodium cyanoborohydride (1 g) are added withstirring. The mixture is left to stand overnight at ambient temperatureand filtered. The filtrate is stirred with 2N hydrochloric acid (50 ml)and then with 2N ammonia (200 ml) for 10 minutes. The methylene chloridephase is removed, washed with water, dried over sodium sulphate andconcentrated. The solid yellow residue is chromatographed on silica gelusing methylene chloride as eluant. The eluants containing the substanceare evaporated and when the residue is recrystallized fromether/petroleum ether, yellow crystals are obtained, m.p. 116°-119° C.

(b) 4'-Amino-4-cyclohexylamino-2-methyl-diphenylsulfone

The title compound of this paragraph is prepared from4-cyclohexylamino-2-methyl-4'-nitro-diphenylsulfone with hydrogen andpalladium/charcoal analogously to Example 25c.

M.p.: 180°-183° C.

EXAMPLE 27 4'-Amino-2-methyl-4-n-propylamino-diphenylsulfone

Here, 2-methyl-4'-nitro-4-propylidenamino-diphenylsulfone (1.5 g)(prepared from 4-amino-2-methyl-4'-nitro-diphenylsulfone,propionaldehyde, titanium(IV) chloride and potassium carbonate indichloromethane) is dissolved in methanol (50 ml) and hydrogenated inthe presence of palladium/charcoal (0.5 g) at ambient temperature undera hydrogen pressure of 50 psi until the uptake of hydrogen has ended.After the catalyst is removed, the remaining mother liquor isconcentrated to dryness in vacuo. The residue is chromatographed oversilica gel with methylene chloride as the eluant. When the eluantscontaining the substance are evaporated, colorless crystals areobtained, m.p.: 170°-173° C.

EXAMPLE 28 4'-Amino-2-methyl-4-methylamino-diphenylsulfone

The title compound is prepared from2-methyl-4-methylamino-4'-nitro-diphenylsulfone with hydrogen andpalladium/charcoal analogously to Example 25c.

M.p.: 150°-153° C.

EXAMPLE 29 4-Ethylamino-4'-amino-2-methyl-diphenylsulfone

The title compound is prepared from4-ethylamino-2-methyl-4'-nitro-diphenylsulfone with hydrogen andpalladium/charcoal analogously to Example 25c.

M.p.: 166°-167° C.

EXAMPLE 30 4'Amino-4-isopropylamino-2-methyl-diphenylsulfone

The title compound is prepared from4-isopropylamino-2-methyl-4'-nitro-diphenylsulfone with hydrogen andpalladium/charcoal analogously to Example 25c.

M.p.: 149°-150° C.

EXAMPLE 31 4'-Amino-4-n-hexylamino-2-methyl-diphenylsulfone

The title compound is prepared from4-n-hexylamino-2-methyl-4'-nitro-diphenylsulfone with hydrogen andpalladium/charcoal analogously to Example 25c.

M.p.: 116°-118° C.

EXAMPLE 32 4'-Amino-4-cyclopentylamino-2-methyl-diphenylsulfone

The title compound is prepared from4-cyclopentylamino-2-methyl-4'-nitro-diphenylsulfone with hydrogen andpalladium/charcoal analogously to Example 25c.

M.p.: 176°-178° C.

EXAMPLE 33 4'-Amino-4-dimethylamino-2-methyl-diphenylsulfone

The title compound is prepared from4-dimethylamino-2-methyl-4'-nitro-diphenylsulfone with hydrogen andpalladium/charcoal analogously to Example 25c.

M.p.: 221°-223° C.

EXAMPLE 34 4'-Amino-4-n-hexylamino-2-methyl-diphenylsulfone

The title compound is prepared from4'-acetamino-4-(N-n-hexyl-N-tosyl-amino)-2-methyl-diphenylsulfone withphenol and hydrobromic acid analogously to Example 6.

M.p.: 116°-118° C.

EXAMPLE 35 4'-Amino-4-isopropylamino-2-methyl-diphenylsulfone

The title compound is prepared from4'-acetamino-4-(N-isopropyl-tosyl-amino)-2-methyl-diphenylsulfone withphenol and hydrobromic acid analogously to Example 6.

M.p.: 149°-150° C.

EXAMPLE 36 4'-Amino-2-chloro-4-cyclohexylamino-diphenylsulfone

The title compound is prepared from4'-acetamino-2-chloro-4-cyclohexyl-amino-diphenylsulfone and 3Nhydrochloric acid analogously to Example 22c.

M.p.: 197°-199° C.

EXAMPLE 37

By hydrolysis of a corresponding compound of formula IIIa ##STR17## Thefollowing compounds are obtained analogously to Example 22c:

    ______________________________________                                         ##STR18##       melting point                                                ______________________________________                                        NHCH.sub.3      150-153°                                               NHC.sub.2 H.sub.5                                                                             166-167°                                               NHC.sub.3 H.sub.7                                                                             170-173°                                               NHisoC.sub.3 H.sub.7                                                                          149-150°                                               NHC.sub.6 H.sub.13                                                                            116-118°                                               NHCyclopentyl   176-178°                                               NHCyclohexyl    180-183°                                               N(CH.sub.3).sub.2                                                                             221-223°                                               ______________________________________                                    

EXAMPLE 38 4-Ethylamino-4'-amino-2-hydroxymethyl-diphenylsulfone

The title compound is prepared from4-ethylamino-4'-amino-2-methoxycarbonyl-diphenylsulfone and lithiumaluminium hydride analogously to Example 17.

M.p.: 148°-151°.

EXAMPLE 39 4'Amino-2-methylamino-4-n-propylamino-diphenylsulfone

The title compound is prepared from4'-acetamino-2-methylamino-4-n-propylamino-diphenylsulfone and 20%hydrochloric acid analogously to Example 22c.

M.p.: 142°-143° C.

EXAMPLE I Tablets containing 4,4'-diamino-2-cyano-diphenylsulfoneComposition

    ______________________________________                                        1 Tablet contains:                                                            ______________________________________                                        Active substance        100.0  mg                                             Corn starch, suitable for                                                                             60.0   mg                                             making directly into tablets                                                  Lactose, suitable for making                                                                          38.0   mg                                             directly into tablets                                                         Magnesium stearate      2.0    mg                                                                     200.0  mg                                             ______________________________________                                    

Preparation

The substances re evenly mixed and compressed to form tablets.

EXAMPLE II Tablets containing 4,4'-diamino-2-cyano-diphenylsulfone

    ______________________________________                                        1 Tablet contains:                                                            ______________________________________                                        Active substance        200.0  mg                                             Corn starch, suitable for                                                                             120.0  mg                                             making directly into tablets                                                  Lactose, suitable for making                                                                          76.0   mg                                             directly into tablets                                                         Magnesium stearate      4.0    mg                                                                     400.0  mg                                             ______________________________________                                    

Preparation

As in Example I.

EXAMPLE III Coated tablets containing4,4'-diamino-2-cyano-diphenylsulfone and pyrimethamine

    ______________________________________                                        1 Tablet core contains:                                                       ______________________________________                                        Active substance        50.0   mg                                             Pyrimethamine           6.25   mg                                             Corn starch, suitable for                                                                             40.0   mg                                             making directly into tablets                                                  Lactose, suitable for making                                                                          22.75  mg                                             directly into tablets                                                         Magnesium stearate      1.0    mg                                                                     120.0  mg                                             ______________________________________                                    

Preparation

As in Example I.

Coating

The cores are coated by known methods with a coating of sugar and talc(30 mg total).

EXAMPLE IV Tablets containing 4,4'-diamino-2-cyano-diphenylsulfone andpyrimethamine

    ______________________________________                                        1 Tablet contains:                                                            ______________________________________                                        Active substance        100.0  mg                                             Pyrimethamine           12.5   mg                                             Corn starch, suitable for                                                                             60.0   mg                                             making directly into tablets                                                  Lactose, suitable for making                                                                          25.5   mg                                             directly into tablets                                                         Magnesium stearate      2.0    mg                                                                     200.0  mg                                             ______________________________________                                    

Preparation

As in Example I.

EXAMPLE V Ampoules containing 4,4'-diamino-2-cyano-diphenylsulfone (i.m.and s.c. crystal suspension)

    ______________________________________                                        1 Ampoule contains:                                                           ______________________________________                                        Active substance        100.0  mg                                             Sodium chloride         15.0   mg                                             Doubly distilled water ad.                                                                            3.0    ml                                             ______________________________________                                    

Preparation

The active substance is finely ground (particle size<5 μm). Thesubstance is homogenously distributed in the sodium chloride solution.The suspension is transferred into ampoules (3 ml) and sterilized for 20minutes at 121° C.

EXAMPLE VI Ampoules containing 4,4'-diamino-2-cyano-diphenylsulfone(i.m. and s.c. crystal suspension) and pyrimethamine (combination withpyrimethamine)

    ______________________________________                                        1 Ampoule contains:                                                           ______________________________________                                        Active substance        100.0  mg                                             Pyrimethamine           12.5   mg                                             Sodium chloride         15.0   mg                                             Doubly distilled water ad.                                                                            3.0    ml                                             ______________________________________                                    

Preparation

The active substances are finely ground (particle size<5μ). Thesubstance are homogeneously distributed in the sodium chloride solution.The suspension is transferred into ampules (3 ml) and sterilized for 20minutes at 121° C.

What is claimed is:
 1. A compound of formula: ##STR19## wherein R₁ ishydrogen, C₁ -C₃ alkyl and R₂ is hydroxy C₁ -C₃ alkyl, C₁ -C₃ alkylcarbonyl or cyano, or a non-toxic, pharmaceutically acceptable saltthereof.
 2. The compound of claim 1,4,4'-diamino-2-hydroxymethyldiphenylsulfone or a non-toxic,pharmaceutically acceptable salt thereof.
 3. The compound of claim 1,4,4'-diamino-2-(1-hydroxyethyl)diphenylsulfone or a nontoxic,pharmaceutically acceptable salt thereof.
 4. The compound of claim 1,4,4'-diamino-2-cyanodiphenylsulfone or a nontoxic, pharmaceuticallyacceptable salt thereof.
 5. The compound of claim 1,4,4'-diamino-2-methylcarbonyldiphenylsulfone or a nontoxic,pharmaceutically acceptable salt thereof.
 6. The compound of claim 4,4'-amino-2-methyl-4-n-propylaminodiphenylsulfone or a nontoxic,pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition of matter suitable for the treatment of infections inwarm-blooded animal comprising a therapeutically effective amount of acompound as recited in claim 1 and a nontoxic, pharmaceuticallyacceptable carrier.
 8. A method for treating infection in a warm-bloodedanimal which comprises administering to said animal a therapeuticallyeffective amount of a compound as recited in claim
 1. 9. The method ofclaim 1 wherein the infection is a bacterial infection.
 10. The methodof claim 1 wherein the infection is a mycobacterial infection.
 11. Themethod of claim 1 wherein the infection is a plasmodia infection.